99mTc-DTB-Antifol-Pteroyls (RadioDAPs): Theranostics for Rheumatoid Arthritis

描述（由申请人提供）：类风湿性关节炎（RA）在美国有210万人发生，与进行性关节破坏、功能残疾和预期寿命下降有关。没有滑膜炎症就不会发生关节破坏。类风湿性关节炎的治疗是为了抑制炎症，目的是建立一个缓解状态。现在有证据表明，活跃的亚临床滑膜炎和进行性关节破坏发生在患者中，尽管持续的药物治疗和明显的临床缓解符合临床标准。这些数据表明，在美国有超过150万患者面临持续关节破坏的风险。即使使用目前最有效的抗风湿药物（DMARDs），大多数患者也无法达到缓解。因此，即使亚临床滑膜炎可以常规检测到，在大多数患者中，使用目前可用的DMARDs设备完全根除关节炎症可能是不可能的。因此，需要在诊断和治疗方法方面进行重大的范式转变。甲氨蝶呤（MTX）是治疗类风湿性关节炎的首选药物，然而，约80%的患者未能达到临床缓解，主要原因是(i)治疗指数窄导致的剂量限制性毒性，以及（ii）不完全和高度可变的细胞摄取。为了提高患者临床和亚临床关节炎症的根除率，我们的目标是寻求一种改进现有金标准DMARD的策略。2006年，美国有3969,000张MTX处方，新的抗叶酸DMARD标准的潜在影响预计将是重大的，可能影响成千上万的RA患者。我们建议开发和测试一系列新的治疗药物99mTc- dtb - antifolo - teroyls (RadioDAPs)，我们假设它将允许高度靶向和集中递送抗叶酸（如氨喋呤，AMT）和99mTc放射性核素到亚临床滑膜炎的部位，通过SPECT成像进行治疗和诊断。我们的长期假设是，治疗性RadioDAP(1)将通过高度靶向和高强度地向明显和亚临床滑膜炎症部位递送抗叶酸剂，显著提高RA的缓解率；(2)将更早、更特异性地检测亚临床滑膜炎，随着时间的推移进一步监测治疗反应，并将个体患者的反应与药物递送联系起来。这项为期两年的实验计划旨在通过使用叶酸转运的体外模型为其化学组装和细胞摄取奠定初步基础，从而快速启动radiodap的开发。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) occurs in 2,100,000 people in the United States, and is associated with progressive joint destruction, functional disability and decreased life expectancy. Joint destruction does not occur without synovial inflammation. The treatment of RA is directed to suppressing inflammation, with the aim of establishing a state of remission. There is now evidence that active subclinical synovitis and progressive joint destruction occurs in patients despite ongoing drug therapy and apparent clinical remission by clinical criteria. These data suggest that well over 1,500,000 patients in United States are at risk for continued joint destruction. Even with the most effective disease-modifying antirheumatic drugs (DMARDs) currently available, the majority of patients fail to achieve remission. Thus, even if subclinical synovitis could be routinely detected, completely eradicating joint inflammation in most patients is likely to be untenable using the currently available armamentarium of DMARDs. A major paradigm shift in diagnostic and therapeutic approach is therefore required. Methotrexate (MTX) is the drug of first choice in treating RA, however, it fails to achieve clinical remission in about 80% of patients mainly because of (i) dose-limiting toxicities due to its narrow therapeutic index, and (ii) incomplete and highly variable cellular uptake. To increase the rate of eradicating clinical and subclinical joint inflammation in patients, we aim to pursue a strategy that will improve on the existing goldstandard DMARD. With 3,969,000 prescriptions for MTX in the United States in 2006, the potential impact of a new antifolate DMARD standard would be expected to be major, potentially affecting hundreds of thousands of patients with RA. We propose to develop and test a series of novel theranostic 99mTc-DTB- Antifol-Pteroyls (RadioDAPs) that we hypothesize will allow the highly targeted and concentrated delivery of antifolate (e.g. aminopterin, AMT) and 99mTc radionuclide to sites of subclinical synovitis for treatment and diagnosis by SPECT imaging. Our long-term hypotheses are that a theranositic RadioDAP (i) will significantly increase the rate of remission in RA through highly targeted and intense delivery of antifolate to sites of overt and subclinical synovial inflammation, and (ii) will detect subclinical synovitis earlier and with greater specificity, with the further ability to monitor for response to therapy over time, and relate this response in an individual patient to delivery of the agent. The two-year experimental plan in this SBIR Grant proposal aims to jumpstart the development of RadioDAPs by laying the initial groundwork for their chemical assembly and cellular uptake using in vitro models of folate transport. PUBLIC HEALTH RELEVANCE: Narrative Rheumatoid arthritis (RA) occurs in 2,100,000 people in the United States, and is associated with progressive joint destruction, functional disability and decreased life expectancy. The proposed RadioDAP technology will be used to simultaneously improve RA therapy and diagnosis.